Novel crystal forms of atorvastatin hemi-calcium and processes for their preparation as well as novel processes for preparing other forms

ABSTRACT

The present invention provides novel forms of atorvastatin designated Forms VI, VII, VIII, IX, IXa, X, XI, XII, XIV, XVI and XVII and novel processes for their preparation as well as processes for preparing atorvastatin Forms I, II, IV, V and amorphous atorvastatin.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part application of U.S.application Ser. No. 09/997,126, filed on Nov. 29, 2001 and claims thebenefit of provisional applications Ser. Nos. 60/250,072, filed Nov. 30,2000; 60/267,897, filed Feb. 9, 2001; 60/281,872, filed Apr. 5, 2001;60/312,144, filed Aug. 13, 2001; 60/326,529, filed Oct. 1, 2001;60/357,181, filed Feb. 15, 2002 and 60/425,325, filed Nov. 12, 2002, allof which are incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to crystalline polymorphic forms ofatorvastatin hemi-calcium and novel processes for preparing crystallineforms of atorvastatin hemi-calcium.

BACKGROUND OF THE INVENTION

Atorvastatin,([R—(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoicacid), depicted in lactone form in formula (J) and its calcium salt offormula (II) are well known in the art, and described, inter alia, inU.S. Pat. Nos. 4,681,893, 5,273,995, and in copending U.S. Ser. No.60/166,153, filed Nov. 17, 2000, all of which are herein incorporated byreference.

Processes for preparing atorvastatin and its hemi-calcium salt are alsodisclosed in U.S. Patent Application Publication No. 2002/0099224; U.S.Pat. Nos. 5,273,995; 5,298,627; 5,003,080; 5,097,045; 5,124,482;5,149,837; 5,216,174; 5,245,047, 5,280,126; Baumann, K. L. et al. Tet.Lett. 1992, 33, 2283-2284, which are hereby incorporated by reference intheir entirety and in particular for their teachings related to thepreparation of atorvastatin and atorvastatin hemi-calcium.

Atorvastatin is a member of the class of drugs called statins. Statindrugs are currently the most therapeutically effective drugs availablefor reducing low density lipoprotein (LDL) particle concentration in theblood stream of patients at risk for cardiovascular disease. A highlevel of LDL in the bloodstream has been linked to the formation ofcoronary lesions which obstruct the flow of blood and can rupture andpromote thrombosis. Goodman and Gilman, The Pharmacological Basis ofTherapeutics 879 (9th ed. 1996). Reducing plasma LDL levels has beenshown to reduce the risk of clinical events in patients withcardiovascular disease and patients who are free of cardiovasculardisease but who have hypercholesterolemia. Scandinavian SimvastatinSurvival Study Group, 1994; Lipid Research Clinics Program, 1984a,1984b.

The mechanism of action of statin drugs has been elucidated in somedetail. They interfere with the synthesis of cholesterol and othersterols in the liver by competitively inhibiting the3-hydroxy-3-methyl-glutaryl-coenzyme A reductase enzyme (“HMG-CoAreductase”). HMG-CoA reductase catalyzes the conversion HMG tomevalonate, which is the rate determining step in the biosynthesis ofcholesterol, and so, its inhibition leads to a reduction in theconcentration of cholesterol in the liver. Very low density lipoprotein(VLDL) is the biological vehicle for transporting cholesterol andtriglycerides from the liver to peripheral cells. VLDL is catabolized inthe peripheral cells which releases fatty acids which may be stored inadopcytes or oxidized by muscle. The VLDL is converted to intermediatedensity lipoprotein (IDL), which is either removed by an LDL receptor,or is converted to LDL. Decreased production of cholesterol leads to anincrease in the number of LDL receptors and corresponding reduction inthe production of LDL particles by metabolism of IDL.

Atorvastatin hemi-calcium salt trihydrate is marketed under the nameLIPITOR by Warner-Lambert Co. Atorvastatin was first disclosed to thepublic and claimed in U.S. Pat. No. 4,681,893. The hemi-calcium saltdepicted in formula (II) is disclosed in U.S. Pat. No. 5,273,995. The'995 patent teaches that the hemi-calcium salt is obtained bycrystallization from a brine solution resulting from the transpositionof the sodium salt with CaCl₂ and further purified by recrystallizationfrom a 5:3 mixture of ethyl acetate and hexane.

The present invention provides new crystal forms of atorvastatinhemi-calcium in both solvated and hydrated states. The occurrence ofdifferent crystal forms (polymorphism) is a property of some moleculesand molecular complexes. A single molecule, like the atorvastatin informula (I) or the salt complex of formula (II), may give rise to avariety of solids having distinct physical properties like meltingpoint, X-ray diffraction pattern, infrared absorption fingerprint andNMR spectrum. The differences in the physical properties of polymorphsresult from the orientation and intermolecular interactions of adjacentmolecules (complexes) in the bulk solid. Accordingly, polymorphs aredistinct solids sharing the same molecular formula yet having distinctadvantageous and/or disadvantageous physical properties compared toother forms in the polymorph family. One of the most important physicalproperties of pharmaceutical polymorphs is their solubility in aqueoussolution, particularly their solubility in the gastric juices of apatient. For example, where absorption through the gastrointestinaltract is slow, it is often desirable for a drug that is unstable toconditions in the patient's stomach or intestine to dissolve slowly sothat it does not accumulate in a deleterious environment. On the otherhand, where the effectiveness of a drug correlates with peak bloodstreamlevels of the drug, a property shared by statin drugs, and provided thedrug is rapidly absorbed by the GI system, then a more rapidlydissolving form is likely to exhibit increased effectiveness over acomparable amount of a more slowly dissolving form.

Crystalline Forms I, II, III and IV of atorvastatin hemi-calcium are thesubjects of U.S. Pat. Nos. 5,959,156 and 6,121,461 assigned toWarner-Lambert and crystalline atorvastatin hemi-calcium Form V isdisclosed in commonly-owned International Publication No. WO 01/36384(PCT Application No. PCT/US00/31555). There is an assertion in the '156patent that Form I possesses more favorable filtration and dryingcharacteristics than the known amorphous form of atorvastatinhemi-calcium. According to the '156 patent, Form I is characterized bypowder X-ray diffraction pattern having peaks at 9.150, 9.470, 10.266,10.560, 11.853, 12.195, 17.075, 19.485, 21.626, 21.960, 22.748, 23.335,23.734, 24.438, 28.915 and 29.234 degrees two-theta.

Commonly owned, co-pending U.S. Patent Application No. 2002/0115709discloses atorvastatin hemi-calcium Form VII, processes for preparing itand pharmaceutical compositions containing it. The '709 patent is herebyincorporated by reference in its entirety.

Although Form I remedies some of the deficiencies of the amorphousmaterial in terms of manufacturability, there remains a need for yetfurther improvement in these properties as well as improvements in otherproperties such as flowability, vapor impermeability and solubility.Further, the discovery of new crystalline polymorphic forms of a drugenlarges the repertoire of materials that a formulation scientist haswith which to design a pharmaceutical dosage form of a drug with atargeted release profile or other desired characteristic.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a characteristic powder X-ray diffraction pattern ofatorvastatin hemi-calcium Form VI obtained using a conventional X-raygenerator with a copper anode.

FIG. 2 is a characteristic powder X-ray diffraction pattern ofatorvastatin hemi-calcium Form VII obtained using a conventional X-raygenerator with a copper anode.

FIG. 3 is a characteristic powder X-ray diffraction pattern ofatorvastatin hemi-calcium Form VIII obtained using a conventional X-raygenerator with a copper anode.

FIG. 4 is a characteristic powder X-ray diffraction pattern ofatorvastatin hemi-calcium Form VIII obtained using a synchrotron X-raysource.

FIG. 5 is a characteristic solid state ¹³C NMR spectrum of atorvastatinForm VIII.

FIG. 6 is a characteristic powder X-ray diffraction pattern ofatorvastatin hemi-calcium Form IX obtained using a conventional X-raygenerator with a copper anode.

FIG. 7 is a characteristic powder X-ray diffraction pattern ofatorvastatin hemi-calcium Form IX obtained using a synchrotron X-raysource.

FIG. 8 is a characteristic solid state ¹³C NMR spectrum of atorvastatinForm IX.

FIG. 9 is a characteristic powder X-ray diffraction pattern ofatorvastatin hemi-calcium Form IXa obtained using a conventional X-raygenerator with a copper anode.

FIG. 10 is a characteristic powder X-ray diffraction pattern ofatorvastatin hemi-calcium Form X obtained using a conventional X-raygenerator with a copper anode.

FIG. 11 is a characteristic powder X-ray diffraction pattern ofatorvastatin hemi-calcium Form X obtained using a synchrotron X-raysource.

FIG. 12 is a characteristic solid state ¹³C NMR spectrum of atorvastatinhemi-calcium Form X.

FIG. 13 is a characteristic powder X-ray diffraction pattern ofatorvastatin hemi-calcium Form XI obtained using a conventional X-raygenerator with a copper anode.

FIG. 14 is an overlay of typical powder X-ray diffraction patterns ofatorvastatin hemi-calcium Form XII obtained using a conventional X-raygenerator with a copper anode.

FIG. 15 is a characteristic powder X-ray diffraction pattern ofatorvastatin hemi-calcium Form XIV obtained using a conventional X-raygenerator with a copper anode.

FIG. 16 is a characteristic powder X-ray diffraction pattern ofatorvastatin hemi-calcium Form XVI obtained using a conventional X-raygenerator with a copper anode.

FIG. 17 is a characteristic powder X-ray diffraction pattern ofatorvastatin hemi-calcium Form XVII.

SUMMARY OF THE INVENTION

The present invention provides new atorvastatin hemi-calcium solvatesand hydrates.

The present invention provides a novel crystalline form of atorvastatinhemi-calcium denominated Form VI and novel processes for itspreparation.

In another aspect, the present invention provides a novel crystallineform of atorvastatin hemi-calcium denominated Form VIII and novelprocesses for its preparation.

In another aspect, the present invention provides a novel crystallineform of atorvastatin hemi-calcium denominated Form IX and novelprocesses for its preparation.

In another aspect, the present invention provides a novel crystallineform of atorvastatin hemi-calcium denominated Form IXa and novelprocesses for its preparation.

In another aspect, the present invention provides a novel crystallineform of atorvastatin hemi-calcium denominated Form X and novel processesfor its preparation.

In another aspect, the present invention provides a novel crystallineform of atorvastatin hemi-calcium denominated Form XI and novelprocesses for its preparation.

In another aspect, the present invention provides a novel crystallineform of atorvastatin hemi-calcium denominated Form XII and novelprocesses for its preparation.

In another aspect, the present invention provides a novel crystallineform of atorvastatin hemi-calcium denominated Form XIV and novelprocesses for its preparation.

In another aspect, the present invention provides a novel crystallineform of atorvastatin hemi-calcium denominated Form XV and novelprocesses for its preparation.

In another aspect, the present invention provides a novel crystallineform of atorvastatin hemi-calcium denominated Form XVI and novelprocesses for its preparation:

In another aspect, the present invention provides a novel crystallineform of atorvastatin hemi-calcium denominated Form XVII and novelprocesses for its preparation another aspect, the present inventionprovides novel processes for preparing atorvastatin hemi-calcium Form I.

In another aspect, the present invention provides novel processes forpreparing atorvastatin hemi-calcium Form II.

In another aspect, the present invention provides novel processes forpreparing atorvastatin hemi-calcium Form IV.

In another aspect, the present invention provides novel processes forpreparing atorvastatin hemi-calcium Form V.

In another aspect, the present invention provides novel processes forpreparing amorphous atorvastatin hemi-calcium.

In another aspect, the invention provides compositions and dosage formscomprising atorvastatin hemi-calcium Forms VI, VII, VIII, IX, X, XI,XIa, XII, XIV, XVI, XVII and their mixtures.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Some crystalline forms of atorvastatin hemi-calcium of the presentinvention exist in a solvated state and hydrated state. Hydrates havebeen analyzed by Karl-Fisher and thermogravimetric analysis.

Powder X-ray diffraction (“PXRD”) analysis employing conventionalCuK_(α) radiation was performed by methods known in the art using aSCINTAG powder X-ray diffractometer model X'TRA equipped with asolid-state detector. Copper radiation of λ=1.5418 Å was used.Measurement range: 2-40 degrees 2θ. The sample was introduced using around standard aluminum sample holder with round zero background quartzplate in the bottom. Powdered samples were gently ground and filled inthe round cavity of the sample holder by pressing with a glass plate.

PXRD analysis using a synchrotron X-ray source was performed at theNational Synchrotron Light Source of the Brookhaven National Laboratory(diffractometer station X3B1). Samples were loosely packed intothin-walled glass capillaries. X-ray radiation was approximately 1.15 Å.Since the wavelength of incident light does correspond to the wavelengthmost commonly used in conventional PXRD analysis, X-ray peak positionsin the diffraction patterns obtained from the synchrotron source areexpressed in terms of d spacings, which are invariant with changes inwavelength of the X-radiation used to produce the pattern. The scanwidth was from 1 to 20 degrees 2θ. The resolution of the spectra is inthe range of 0.01 to 0.03 degrees full width at half maximum. Thepositions of well resolved peaks are accurate to within 0.003 to 0.01degrees.

The CP/MAS ¹³C NMR measurements were made at 125.76 MHz and wereperformed on a Bruker DMX-500 digital FT NMR spectrometer equipped witha BL-4 CP/MAS probehead and a High Resolution/High Performance ¹Hpreamplifier for solids: spin rate 5.0 kHz, pulse sequence SELTICS,sample holder: Zirconia rotor 4 mm diameter.

Atorvastatin hemi-calcium Form VI is characterized by a powder X-raydiffraction pattern (FIG. 1) with peaks at 3.5, 5.1, 7.7, 8.2, 8.7,10.0, 12.5, 13.8, 16.2, 17.2, 17.9 18.3, 19.5, 20.4, 20.9, 21.7, 22.4,23.2, 24.3, 25.5±0.2 degrees two-theta. The most characteristic peak isobserved at 19.5±0.2 degrees two-theta The PXRD pattern of Form VI wastaken using a Phylips diffractometer similar to the SCINTAGinstrumentation described above.

Atorvastatin hemi-calcium Form VI may be obtained by dissolving anyother form of atorvastatin hemi-calcium, preferably Form I, in acetoneand then precipitating Form VI by addition of an anti-solvent,preferably water.

Atorvastatin hemi-calcium Form VII is characterized by a powder X-raydiffraction pattern (FIG. 2) having two broad peaks, one in the range18.5-21.8 and the other in the range of 21.8-25.0 degrees 2θ, and otheradditional broad peaks at 4.7, 7.8, 9.3, 12.0, 17.1, 18.2±0.2 degrees2θ. Samples of Form VII may contain up to 12% water.

Form VII is readily distinguished from known forms of atorvastatinhemi-calcium by the broad peaks at 7.8 and 9.3±0.2 degrees 2θ. Forinstance, Form I has peaks at 9.2, 9.5, 10.3, 10.6, 11.0 and 12.2degrees 2θ according to the information provided in U.S. Pat. No.5,969,156. In this region, Form II has two sharp peaks at 8.5 and 9.0degrees 2θ and Form IV has one strong peak at 8.0 degrees 2θ. The otherbroad peaks in the region of 15-25 degrees distinguish Form VII from allother forms. Forms I, III and IV all have sharp peaks in this region.

Atorvastatin hemi-calcium Form VII may be prepared by treatingatorvastatin calcium Forms I or V with ethanol, preferably absoluteethanol, at room temperature to reflux temperature for a period of fromabout 1 h to about 24 h, preferably 2.5-16 h. If the process is carriedout in refluxing EtOH, the conversion is complete in about 2.5 h. If theprocess is carried out at room temperature a longer period is required.

Atorvastatin hemi-calcium Form VIII is characterized by a powder X-raydiffraction pattern (FIG. 3) obtained using conventional CuK_(α)radiation having peaks at 4.8, 5.2, 5.9, 7.0, 8.0, 9.3, 9.6, 10.4, 11.9,16.3, 17.1 (broad), 17.9, 18.6, 19.2, 20.0, 20.8, 21.1, 21.6, 22.4,22.8, 23.9, 24.7, 25.6, 26.5, 29.0±0.2 degrees two-theta. The mostcharacteristic peaks are at 6.9, 9.3, 9.6, 16.3, 17.1, 19.2, 20.0, 21.6,22.4, 23, 9, 24.7, 25.6, and 26.5±0.2 degrees 2θ. Samples ofatorvastatin hemi-calcium Form VIII were found to contain up to 7% waterby Karl Fisher.

Form VIII is readily distinguished from Forms I-IV by its characteristicsharp peaks at 9.3 and 9.6 degrees 2θ. According to the informationprovided in U.S. Pat. No. 5,969,156, Form I has one medium peak at 6.9and sharp peaks at 9.2, 9.5, 10.3, 10.6, 11.0 and 12.2±0.2 degrees 2θ.Form IV is said to have two peaks at 8.0 and 9.7 degrees 2θ. Form II issaid to have in this region two sharp peaks at 8.5 and 9.0 degrees 2θ.Form III has in this region one strong sharp peak at 8.7 degrees 2θaccording to the information provided in U.S. Pat. No. 6,121,461. Thefeatures are not observed in the Form VIII PXRD pattern. Further, thereis in the PXRD pattern of Form VIII one sharp, medium intensity peak at7.0 which is well distinguished from other peaks in the region. Acomparison of the PXRD pattern of Form VIII with the patterns of FormsI-IV reveals that this feature of the Form VIII pattern is distinctive.

Other peaks in the Form VIII pattern that are unique to this form arethe two strong and sharp peaks at 19.2 and 20.0 degrees 2θ. In thisregion, Form I has sharp peaks at 21.6, 22.7, 23.3 and 23.7 degrees 2θaccording to the information provided in the '156 patent. Form IV issaid to have peaks at 18.4 and 19.6 degrees 2θ, while Form II has twomain peaks at 17.0 and 20.5 and Form III has peaks at 17.7, 18.2, 18.9,20.0 and 20.3±0.2 degrees 2θ.

Synchrotron X-ray powder diffraction analysis was performed on Form VIIIto determine its crystal system and unit cell dimensions. Form VIII hasa monoclinic unit cell with lattice dimensions: a=18.55-18.7 Å,b=5.52-5.53 Å, c=31.0-31.2 Å and angle β between the a and c axes of97.5-99.5°. The unit cell parameters were determined using the Le Bailmethod.

The diffractogram of FIG. 4 obtained using a synchrotron X-ray sourcehas many sharp well resolved peaks. The d-spacings of some of the moreprominent peaks are listed in Table 1, along with the positions in unitsof two-theta that the peaks would have using CuK_(α) radiation of 1.5418Å.

TABLE 1 d (Å) 2θ^(a) 30.81 2.87 18.46 4.79 16.96 5.21 15.39 5.74 14.905.93 12.78 6.92 11.05 8.00 9.58 9.23 9.22 9.59 7.42 11.93 6.15 14.405.43 16.32 4.62 19.21 4.44 20.00 3.98 22.34 ^(a)Calculated from d forCuK_(a) radiation

Because of the natural variation between independent samples andmeasurements, the peak positions may deviate from the reported positionsby as much as 0.5% of the d values. There may be larger shifts if thematerial undergoes size reduction such as micronization.

Atorvastatin hemi-calcium Form VIII produced the solid-state ¹³C NMRspectrum shown in FIG. 5. Form VIII is characterized by the followingsolid-state ¹³C nuclear magnetic resonance chemical shifts in ppm: 17.8,20.0, 24.8, 25.2, 26.1, 40.3, 40.8, 41.5, 43.4, 44.1, 46.1, 70.8, 73.3,114.1, 116.0, 119.5, 120.1, 121.8, 122.8, 126.6, 128.8, 129.2, 134.2,135.1, 137.0, 138.3, 139.8, 159.8, 166.4, 178.8, 186.5. Form VIII ischaracterized by a solid-state ¹³C nuclear magnetic resonance having thefollowing chemical shifts differences between the lowest ppm resonanceand other resonances: 2.2, 7.0, 7.4, 8.3, 22.5, 23.0, 23.7, 25.6, 26.3,28.3, 53.0, 55.5, 96.3, 98.2, 101.7, 102.3, 104.0, 105.0, 108.8, 111.0,111.4, 116.4, 117.3, 119.2, 120.5, 122.0, 142.0, 148.6, 161.0 and 168.7.The chemical shifts reported for Form VIII are averaged from spectrataken of four samples of Form VIII. Characteristic parts of the patternare found at 24-26 ppm (aliphatic range), 119-140 ppm (aromatic range)and other regions. The shift values are accurate to within ±0.1 ppm,except for the carbonyl peak at 178.8 ppm which has a fluctuation of±0.4 ppm.

Atorvastatin hemi-calcium Form VIII can exist as an ethanol solvatecontaining up to about 3% ethanol by weight.

The following methods have been found suitable for generating Form VIII.This form may, however, also be accessible by empirical development andby routine modification of these procedures.

Atorvastatin hemi-calcium Form VIII may be obtained by slurryingatorvastatin hemi-calcium in a mixture of ethanol and water at elevatedtemperature, preferably about 78-80° C. The slurrying procedure may beincorporated into the last step of a process for preparing atorvastatinhemi-calcium, which typically is generation of the hemi-calcium saltfrom the atorvastatin free acid or lactone by treatment with a source ofcalcium ion. In such a combined procedure the salt is generated in asolvent system comprising ethanol and water. Conveniently, afterprecipitation of the atorvastatin hemi-calcium salt by an additionalamount of water, the salt may be slurried in the reaction mixture for aperiod of several hours, preferably from about 6 to about 16 hours toobtain atorvastatin hemi-calcium Form VIII.

Form VIII also may be obtained starting from Form V by treating Form Vwith a mixture of EtOH:H₂O, preferably in the ratio of about 5:1 at anelevated temperature below reflux, preferably 78-80° C. An especiallypreferred EtOH:H₂O mixture contains about 4% by volume water in ethanol.During the heating, atorvastatin Form V gradually dissolves and at thepoint of 78-80° C. turbidity, with or without seeding, is observed. Atthis point the suspension is immediately cooled to room temperature.

Form VIII may be obtained by treating atorvastatin hemi-calcium in EtOH,preferably absolute EtOH, at elevated temperature, preferably boilingEtOH. Under these conditions, the atorvastatin dissolves andreprecipitates. MeOH may be added at reflux. Added MeOH may adverselyaffect the yield, but may improve the chemical purity of the product.Starting materials for preparing Form VIII by this process can becrystalline forms of atorvastatin hemi-calcium, preferably Forms I and Vand mixtures thereof or amorphous atorvastatin hemi-calcium.

The quantity of EtOH or mixture thereof with water is preferably in therange of from about 10 to about 100 ml g⁻¹, more preferably about 20 toabout 80 ml g⁻¹.

We have discovered that atorvastatin hemi-calcium that contains greaterthan 0.1% des-fluoro atorvastatin hemi-calcium and/or greater than 1%trans atorvastatin hemi-calcium may be purified by suspending in asolution of about 96% ethanol and about 4% water at elevatedtemperature, preferably at reflux temperature. Typically, atorvastatinhemi-calcium is recovered with less than 0.07% contamination withdes-fluoro atorvastatin hemi-calcium and less than 0.6% contaminationwith trans atorvastatin hemi-calcium.

Form VIII also may be prepared by suspending atorvastatin hemi-calciumin certain 1-butanol/water and ethanol/water mixtures for a period oftime sufficient to cause the conversion of the atorvastatin hemi-calciumto Form VIII. 1-Butanol/water mixtures should contain about 20%1-butanol by volume at elevated temperature, preferably at refluxtemperature.

It will be appreciated from the description of Form XVII that followsthat conventional drying of Form XVII transforms it into Form VIII. Byconventional drying it is meant the methods of drying routinely used bythose skilled in the art in the pharmaceutical industry. Any drying typeof equipment conventionally used in the pharmaceutical industry issuitable for this purpose. A drying temperature in the range of about40-70° C. (in temperature steps or in one temperature only) ispreferred. The amount of time required to convert Form XVII to Form VIIIdepends on the quantity of material employed. Vacuum may be preferablyused to convert Form XVII to Form VIII by drying. Preparation of FormVIII also may be achieved by drying Form XVII at temperatures lower than40° C., down to room temperature.

Atorvastatin hemi-calcium Form IX is characterized by a powder X-raydiffraction pattern (FIG. 6) with peaks at 4.7, 5.2, 5.7, 7.0, 7.9, 9.4,10.2, 12.0, 17.0, 17.4, 18.2, 19.1, 19.9, 21.4, 22.5, 23.5, 24.8(broad), 26.1, 28.7, 30.0±0.2 degrees two-theta. The most characteristicpeaks of Form IX are at 6.9, 17.0, 17.4, 18.2, 18.6, 19.1, 19.9, 21.4,22.5 and 23.5±0.2 degrees two-theta. Form IX may contain up to 7% water.Form IX also can exist as a butanol solvate containing up to about 5%butanol.

Form IX is readily distinguished by its characteristic sharp peaks at18.6, 19.1, 19.9, 21.4, 22.5, 23.5 degrees 2θ. For comparison, Form Ihas sharp peaks at 21.6, 22.7, 23.3 and 23.7 degrees 2θ, while Form IVhas in this region sharp peaks at 18.4 and 19.6 degrees 2θ and Form IIhas two main peaks at 17.0 and 20.5 degrees 2θ, according to informationin the '156 patent. Form III has in this region peaks at 17.7, 18.3,18.9, 20.0 and 20.3 degrees 2θ. Also, there is in the PXRD pattern ofForm IX, as there is in the pattern of Form VIII, a sharp, welldistinguished medium intensity peak at 7.0 degrees 2θ.

The crystal system and unit cell dimension of Form IX were determinedusing synchrotron X-ray powder diffraction analysis. Form IX has amonoclinic crystal lattice with lattice dimensions: a=18.75-18.85 Å,b=5.525-5.54 Å, c=30.9-31.15 Å and angle 3 between the a and c axes of96.5-97.5°.

The d-spacings of some of the more prominent peaks in the synchrotronX-ray powder diffractogram of FIG. 7 are listed in Table 2, along withthe positions in units of two-theta that the peaks would have usingCuK_(α) radiation.

TABLE 2 d (Å) 2θ^(a) 30.86 2.86 18.67 4.73 16.91 5.23 15.17 5.83 12.666.98 11.20 7.89 9.50 9.31 9.28 9.53 8.63 10.25 7.69 11.51 7.38 11.996.51 13.60 5.45 16.26 5.26 16.86 5.20 17.05 5.12 17.32 4.87 18.22 4.7618.64 4.63 19.17 4.47 19.86 4.14 21.46 4.08 21.78 3.78 23.54 3.73 23.863.62 24.59 3.58 24.87 ^(a)Calculated from d for CuK_(a) radiation

Because of the natural variation between independent samples andmeasurements, the peak positions may deviate from the reported positionsby as much as 0.5% of the d values. There may be larger shifts if thematerial undergoes size reduction such as micronization.

Atorvastatin hemi-calcium Form IX produced the solid-state ¹³C NMRspectrum shown in FIG. 8. Form IX is characterized by the followingsolid-state ¹³C nuclear magnetic resonance chemical shifts in ppm: 18.0,20.4, 24.9, 26.1, 40.4, 46.4, 71.0, 73.4, 114.3, 116.0, 119.5, 120.2,121.7, 122.8, 126.7, 128.6, 129.4, 134.3, 135.1, 136.8, 138.3, 139.4,159.9, 166.3, 178.4, 186.6. Form IX is characterized by a solid-state¹³C nuclear resonance having the following chemical shifts differencesbetween the lowest ppm resonance and other resonances: 2.4, 6.9, 8.1,22.4, 28.4, 53.0, 55.4, 96.3, 98.0, 101.5, 102.2, 103.7, 104.8, 108.7,110.6, 111.4, 116.3, 117.1, 118.8, 120.3, 121.4, 141.9, 148.3, 160.4,168.6. Characteristic parts of the pattern are found at 2426 ppm(aliphatic range), 119-140 ppm (aromatic range) and other regions. Thechemical shifts of Form IX are an average taken from spectra on twosamples of Form IX. The shift values are accurate to within ±0.1 ppm.

Form IX may be prepared by the following processes though this form maybe accessed by empirical development and by routine modification ofthese procedures.

Atorvastatin hemi-calcium Form IX may be prepared by slurryingatorvastatin hemi-calcium in 1-butanol and isolating Form IX by, forexample, filtration or decantation of the butanol, preferably byfiltration. Preferred temperature ranges for the slurrying are from 78°C. to the reflux temperature of the solvent. Recovery of atorvastatinhemi-calcium salt from the slurry can be enhanced by addition of ananti-solvent to the slurry before isolating Form IX. Preferredanti-solvents include isopropanol and n-hexane. Starting materials forpreparing Form IX by this process can be crystalline or amorphousatorvastatin hemi-calcium, preferably Forms I and V and mixturesthereof.

Form IX may be prepared by suspending Form VIII in ethanol, preferablyabsolute ethanol, at room temperature for a period of time sufficient toconvert Form VIII to Form IX, which may range from a few hours to 24hours and typically requires about 16 hours. Thereafter Form IX isrecovered from the suspension. Form IX also may be prepared bymaintaining Form VIII under a humid atmosphere.

Form IX also can be prepared by suspending Form V in a mixture of 50%1-butanol and 50% of another organic solvent(s) like acetone,2-propanol, tetrahydrofuran, 1-propanol and methyl t-butyl ether. Themixture is used in an amount of about 20 milliliters per gram of Form V.The suspension is heated to reflux temperature for about 16 hours, afterwhich time Form V is transformed into Form IX, which can then berecovered from the suspension by conventional means.

It has also been found that suspending atorvastatin hemi-calcium Form Vin mixtures of 1-butanol and water, wherein one or the other diluent ispredominant in the mixture, will yield a more highly pure andcrystalline atorvastatin hemi-calcium product. This product has beendenominated Form IXa. Atorvastatin hemi-calcium Form IXa ischaracterized by its PXRD pattern (FIG. 9), which is similar in somerespects to that of Form IX. However, there are differences between thetwo patterns. The most predominant difference is at 9.5 degreestwo-theta. There, a single strong peak is observed in the PXRD patternof Form IX whereas two strong peaks are observed at 9.3 and 9.5 degreestwo-theta in the Form IXa pattern. In addition, there are small peaks at15.7, 20.5, 21.1, 22.8, 23.8, 24.0, 25.3, 26.4, 26.8, 27.2, 29.2 and31.6±0.2 degrees two-theta in the PXRD pattern of Form IXa.

Atorvastatin hemi-calcium Form IXa is considered to be an especiallycrystalline, filterable and pure material having similar internalstructure to Form IX, hence the designation Form IXa. Form IXa can beprepared by suspending atorvastatin hemi-calcium Form V in mixtures of1-butanol and water in which either the 1-butanol or water constitutesfrom about 85% to about 95%, more preferably about 90%, of the mixture.The suspension can be heated to accelerate conversion of Form V to FormIXa. Sixteen hours at about 85° C. is generally sufficient. Under theseconditions, yields as high as 95% can be obtained and the impurity levelof the material can be significantly reduced. The impurity content ofthe starting atorvastatin hemi-calcium can be reduced by about 50% ormore. For example, Form IX can be obtained in about 0.7% chemical puritywhen starting with Form V of about 1.3% chemical purity. Chemical puritywas measured by high performance liquid chromatography (“HPLC”). HPLCwas performed on a Spherisorb® S5, C8 column, 250×4.6 mm with gradientelution: Solvent A 0.05M KH₃PO₄ adjusted to pH 5 with 1NKOH:acetonitrile: methanol:THF (62:26:8:4); Solvent B: methanol. TheHPLC system was equipped with Waters® pumps and a UV detector set todetect at 254 nm.

Among the specific procedures that can be used there may be mentionedthe following. Form V is suspended in a mixture of 90% 1-butanol and 10%water (v/v). The mixture is used in an amount of about 20 millilitersper gram of Form V. The suspension is refluxed at 90° C. for about 16hours, after which time Form V is transformed into Form IX, which isthen be recovered from the suspension by conventional means, likefiltration.

According to another specific procedure, Form V is suspended in amixture of 10% 1-butanol and 90% water (v/v). The mixture is used in anamount of about 20 milliliters per gram of Form V. The suspension isrefluxed for about 16 hours, after which time Form V is transformed intoForm IX, which is then recovered by conventional means.

The present invention further provides atorvastatin hemi-calcium Form X.Form X is characterized by a powder X-ray diffraction pattern (FIG. 10)having peaks at 4.8, 5.3, 5.9, 9.6, 10.3, 11.5, 12.0, a double peak at16.1 and 16.3, 16.9, 17.4, 18.2, 19.2, 19.4, 20.0, 20.8, 21.6, 22.0,22.8, 23.6, 24.6, 25.0, 25.5, 26.2, 26.8, 27.4, 28.0, 30.3±0.2 degrees2θ. The most characteristic peaks are two peaks at 20.0 and 20.8±0.2degrees 2θ and other peaks at 19.1, 19.4, 22.8, 23.6, 25.0, 28.0,30.3±0.2 degrees 2θ. Form X contains up to 2% ethanol and may contain upto 4% water.

The PXRD pattern of Form X is distinguished from that of Form TV byhaving characteristic peaks at 7.0, 19.9, 20.7, 24.1, 25.0, 28.0 and30.3±0.2 degrees 2θ. These features are clearly distinguished from thoseappearing the corresponding regions of the PXRD patterns of Forms I-IVwhich have been previously described.

The crystal system and unit cell dimension of Form X were determinedusing synchrotron X-ray powder diffraction analysis. Form X has amonoclinic crystal lattice with lattice dimensions: a=18.55-18.65 Å,b=5.52-5.53 Å, c=30.7-30.85 Å and angle β between the a and c axes of95.7-96.7°.

The d-spacings of some of the more prominent peaks in the synchrotronX-ray powder diffractogram of FIG. 11 are listed in Table 3, along withthe positions in units of two-theta that the peaks would have usingCuK_(α) radiation.

TABLE 3 d (Å) 2θ^(a) 30.63 2.88 18.49 4.78 16.66 5.30 15.12 5.85 12.497.08 11.19 7.90 10.20 8.67 9.38 9.43 9.24 9.57 9.13 9.69 8.58 10.31 7.6411.58 7.36 12.02 7.26 12.19 6.81 13.00 6.50 13.62 6.16 14.38 5.91 14.995.24 16.92 5.19 17.08 5.06 17.53 4.86 18.25 4.74 18.72 4.65 19.09 4.6119.25 4.56 19.47 4.12 21.57 4.10 21.95 3.93 22.62 3.90 22.80 3.77 23.60^(a)Calculated from d for CuK_(a) radiation

Because of the natural variation between independent samples andmeasurements, the peak positions may deviate from the reported positionsby as much as 0.5%. There may be larger shifts if the material undergoessize reduction such as micronization.

Atorvastatin hemi-calcium Form X produced the solid-state ¹³C NMRspectrum shown in FIG. 12. Form X is characterized by the followingsolid-state ¹³C nuclear resonance chemical shifts in ppm: 17.7, 18.7,19.6, 20.6, 24.9, 43.4, 63.1, 66.2, 67.5, 71.1, 115.9, 119.5, 1224,126.7, 128.9, 134.5, 138.0, 159.4, 166.2, 179.3, 181.1, 184.3, 186.1.Form X is characterized by a solid-state ¹³C nuclear magnetic resonancehaving the following chemical shifts differences between the lowest ppmresonance and other resonances: 1.0, 1.9, 2.9, 7.2, 25.7, 45.4, 48.5,49.8, 53.4, 98.2, 101.8, 104.7, 109.0, 111.2, 116.8, 120.3, 141.7,148.5, 161.6, 163.4, 166.6, 168.4. Characteristic parts of the patternare found at 24-26 ppm (aliphatic range), 119-140 ppm (aromatic range)and other regions. The chemical shifts of Form X are averaged from threespectra taken of three samples of Form X. The values reported are within±0.1 ppm, except for the carbonyl peak at 179.3 ppm that is accuratewithin ±0.4 ppm.

Atorvastatin hemi-calcium Form X may be prepared by treating crystallineatorvastatin hemi-calcium, preferably Form V or Form I or mixturesthereof, or amorphous atorvastatin hemi calcium with a mixture ofethanol and water, preferably in a ratio of about 5:1, at elevatedtemperature, preferably at reflux temperature, for a period of fromabout half an hour to a few hours, preferably about 1 h. The startingmaterial may be added to the EtOH:water mixture at room temperature,followed by gradual heating of the suspension to reflux. Alternatively,the starting form of atorvastatin hemi-calcium may be added to therefluxing solvent mixture. In either case, the atorvastatin hemi-calciumshould be observed to dissolve in the mixture and then reprecipitate inForm X. The ratio of atorvastatin hemi-calcium to the EtOH:water mixturepreferably ranges from about 1:16 to about 1:25 (g:ml), more preferablyfrom about 1:16 to about 1:21 (g:ml) and most preferably about 1:16(g:ml). Form X may be collected by filtration shortly after cooling toroom temperature or the suspension may be stirred for an addition periodof from about 1 to about 20 hours, more preferably from about 3 to about16 hours, before collecting the Form X.

Atorvastatin hemi-calcium Form X is characterized by a powder X-raydiffraction pattern (FIG. 13) having peaks at 3.2, 3.7, 5.1, 6.3, 7.8,8.6, 9.8, 11.2, 11.8, 12.4, 15.4, 18.7, 19.9, 20.5, 24.0±0.2 degreestwo-theta Form XI may be obtained by suspending atorvastatinhemi-calcium Form V in methyl ethyl ketone (“MEK”) at room temperaturefor a period of time sufficient to cause the conversion of Form V intoForm XI.

Form XI also may be obtained by preparing a gel containing atorvastatinhemi-calcium in isopropyl alcohol and then drying the gel. The gel isbest prepared by saturating isopropyl alcohol with atorvastatinhemi-calcium at reflux temperature and then cooling to room temperature.Extensive stirring at room temperature, as long as or more than 20 h,may be required in order for the gel to form. In the gel state, thesolution is detectably more resistant to stirring and does not poursmoothly. The gel remains flowable in the sense that it can be stirredif sufficient force is applied and would not tear under such force.

Atorvastatin hem i-calcium Form XII is characterized by a powder X-raydiffraction pattern having peaks at 2.7, 8.0, 8.4, 11.8, 18.2, 19.0,19.8, 20.7±0.2 degrees two-theta, and a halo that indicates the presenceof amorphous material. Typical X-ray powder diffraction patterns ofatorvastatin hemi-calcium Form XII are shown in FIG. 14.

Form XII may be prepared directly from the following compound

whose systematic chemical name is[R—(R*,R*)]-2-(4-fluorophenyl)-β,δ-dioxane-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-tert-butylheptanoicester, and which will hereafter be referred to as pyrrole acetonideester or PAE. Form XII is prepared by first subjecting PAE to conditionsthat cleave the acetonide and tert-butyl ester group. Preferredconditions employ aqueous hydrochloric acid, more preferably about 1.5%aqueous hydrochloric acid. The solution of atorvastatin, in either freeacid or lactone form, or mixture thereof, is then treated with calciumhydroxide, preferably a modest excess thereof, more preferably about 1.5equivalents with respect to the PAE. After association of theatorvastatin with dissolved calcium derived from the added hydroxidesalt, any excess calcium hydroxide may be separated by filtration. Oneimportant feature of this process is the subsequent manipulation of thefiltrate. Water is slowly added to the reaction mixture at mildlyelevated temperature, preferably about 65° C., until atorvastatinhemi-calcium precipitates. At that point the temperature is increaseduntil a clear solution is once again attained. The mixture is thenallowed to cool resulting in the precipitation of atorvastatinhemi-calcium. The isolated precipitate is atorvastatin hemi-calcium FormXII.

The present invention further provides a novel polymorph of atorvastatinhemi-calcium that has been denominated Form XIV. Atorvastatinhemi-calcium Form XIV is characterized by a powder X-ray diffractionpattern obtained using conventional CuK_(α) radiation (FIG. 15) havingpeaks at 7.6, 9.8, 16.5, 18.1, 20.0, 20.4, 21.9, 22.4, 23.6, 29.4±0.2degrees two-theta The most characteristic peaks are those at 7.6, 9.8,16.5, 29.4±0.2 degrees two-theta.

In general terms, Form XIV can be obtained from a suspension ofatorvastatin hemi-calcium in water. According to U.S. Pat. No.5,969,156, atorvastatin hemi-calcium Form I precipitates when calciumacetate is added to a solution of atorvastatin sodium in water. It isalso said that Form I can be prepared by suspending amorphousatorvastatin hemi-calcium in water. In the specific example provided,Example 1, a mixture formed from atorvastatin sodium and calcium acetatein water was seeded with Form I shortly after addition of the calciumacetate solution and, thereafter, Form I was obtained.

We have found that suspending atorvastatin hemi-calcium in orprecipitating atorvastatin hemi-calcium from water does not invariablylead to the production of Form I as might be expected after studying the'156 patent. On the contrary, in our hands, suspensions of atorvastatinhemi-calcium in water yield a previously unknown polymorph that we havedenominated Form XIV. Form XIV is readily distinguishable from Form I(which is also obtained by precipitation from water, but with seedingwith Form I) by the peaks at 7.6, 16.5, 20.0 and 19.4 degrees two-theta,which peaks are absent from the PXRD pattern of Form I.

It should be noted that in Example 35, below, the suspension is notstirred or seeded with a crystal of Form I. Atorvastatin hemi-calciumForm XIV can be prepared by suspending atorvastatin hemi-calcium inwater until a fine suspension forms and then allowing the suspension tostand undisturbed until the fine crystals transform substantially intowhite flakes. The flakes can be separated from the suspension byconventional means, like decanting or filtering (either with or withoutsuction and they do not clog the filter) and washing the crystals. Thecrystals of the fine suspension are very small giving the suspension theappearance of an emulsion. The transformation from fine suspension toflakes is readily apparent from visual inspection of the suspension.Preferred process parameters are as follows. The preferred startingmaterial is atorvastatin hemi-calcium Form V. The fine suspensiontypically forms over a period of from about 2 to about 10 hours, onaverage about 5 hours. The fine suspension transforms into white flakesover about one to about five days, with longer time periods beingpreferred for more complete conversion and a more easily filterableproduct. Other conditions which lead to the production of Form XIV maybe discovered but presently the best method known is by suspendingatorvastatin hemi-calcium in water that is not agitated and has not beenseeded with a different polymorph of atorvastatin. Form XIV has beenobtained in our laboratory without seeding of any kind.

Form XIV crystals can be transformed into another crystal form withoutcontact with solvent. This new form has been denominated Form XVI. FormXVI is characterized by a powder X-ray diffraction pattern obtainedusing conventional CuK_(α) radiation (FIG. 16) having peaks at 7.7, 9.9,16.5, 17.7, 18.3, 20.0, 21.9, 29.5±0.2 degrees two-theta. The mostcharacteristic peaks are at 16.5, 21.9; 29.5±0.2 degrees two-theta.

Form XVI may be produced by maintaining Form XIV at from about 20° C. toabout 50° C., preferably about 22° C. or room temperature, andpreferably exposed to air. Preferably, Form XIV is maintained underthese conditions for about three hours. Other conditions under whichForm XVI is formed may be empirically determined. It is only possible togive methods which have so far been found suitable for producing it.

The present invention further provides a hydrated form of atorvastatinhemi-calcium that has been denominated Form XVII. Form XVII has beenisolated as the immediate product obtained by precipitation from wetethanol. As taught by U.S. Patent Application Publication No.2992/0183378 (alternatively, see International Publication No. WO01/36384 of PCT application number PCT/US00/31555), Form VIII can beprepared from a dispersion of Form V in a mixture of 96% ethanol/waterat a temperature of about 70° C. By using this procedure in scales of atleast 1 liter or more, the precipitated material, prior to being dried,is obtained in Form XVII.

Atorvastatin hemi-calcium Form XVII is characterized by a powder X-raydiffraction pattern obtained using conventional CuK_(α) radiation bytypical X-Ray peaks at 19.1, 20.6, 21.4 and 23.6±0.2 degrees two-theta.Additional peaks are observed at 7.8, 9.5, 10.2, 18.2, 19.1, 25.3, 26.2,30.1±0.2 degrees two-theta. Form XVII is also characterized by thetypical powder X-Ray diffraction pattern of FIG. 17. Form XVII isdistinguishable from Form VIII (the material obtained by complete dryingof material obtained by precipitation from 96% ethanol/4% water) by thepeak pattern in the range of 9-10, 18-25 degrees two-theta. Inparticular, Form VIII exhibits two strong peaks at 19.2 and 20.0±0.2degrees 2θ, while Form XVII has one strong peak at 19.1±0.2 degrees 2θ,but no comparably strong peak at 20±0.2 degrees 2θ.

Atorvastatin hemi-calcium Form XVII may be produced by suspendingatorvastatin hemi-calcium Form V in a mixture of 96% ethanol and 4%water (v/v) and heating to about 78-80° C., followed by cooling. FormXVII can be isolated immediately after the material starts toprecipitate in the mixture at reflux temperature, or after all thematerial is precipitated, after the material is cooled down to roomtemperature, or after all the solid is isolated from the mother liquor(for instance by filtration). Although there may be other ways to obtainForm XVI, the best way presently known is to suspend atorvastatinhemi-calcium Form V in at least about 500 milliliters or more of amixture of about 96% ethanol and about 4% water (v/v) and refluxing thesuspension, followed by cooling. The solids are then recovered byconventional means such as filtering or decanting as Form XVII.Additional experimental details are provided in Example 38. The volumeof the reactor should be at least about 1 liter.

The present invention also provides novel processes for preparing knownforms of atorvastatin hemi-calcium.

Form I may be obtained by treating any form of atorvastatin hemi-calciumwith water at room temperature to 100° C. for a period between a few toabout 25 hours, preferably about 16 hours. Preferred starting materialsare Forms V, VII, VIII, IX and X of atorvastatin hemi-calcium.

Form I also may be prepared by sonicating a suspension of atorvastatinhemi-calcium in ethanol, preferably absolute ethanol or in water, atbetween room temperature and the reflux temperature of the solvent for aperiod of a few minutes. Preferably between 1 and 3 minutes.Atorvastatin hemi-calcium Form VII is a preferred starting materialthough other forms may be used as well.

Atorvastatin hemi-calcium Form I may be produced by heating Form XIV toabout 50° C. or above, preferably about 65° C. Preferably, Form XIV ismaintained at elevated temperature for about 15 hours.

Form II may be prepared directly from[R—(R*,R*)]-2-(4-fluorophenyl)-β,δ-dioxane-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-tert-butylheptanoicester (PAE) according to Example 46.

Atorvastatin hemi-calcium Form IV may be prepared by suspending Form Ior Form V in 1-butanol for a period of time sufficient to complete theconversion of Form I or Form V to Form IV and then isolating Form IVfrom the mixture. The conversion may require a prolonged perioddepending on temperature and other conditions. The conversion typicallytakes about 24-72 hours at room temperature.

Form IV also may be obtained by suspending Form V in EtOH/H₂O at 50° C.for a period of time sufficient to cause the conversion of Form V toForm IV and then recovering Form IV from the suspensions. PreferredEtOH/H₂O mixtures contain about 15% H₂O.

Form IV also may be obtained by suspending atorvastatin hemi-calciumForm V in methanol for a period of time sufficient to cause theconversion of Form V to Form IV. The rate of conversion is sensitive totemperature and may take from about 1 to about 25 hours under typicallaboratory conditions. The conversion requires about 16 hours, at roomtemperature. The conversion may be conducted at elevated temperature upto the reflux temperature of the solvent.

Form V may be prepared from PAE according to the process described withreference to the preparation of atorvastatin hemi-calcium Form XII. FormV may be obtained by drying Form XII at about 65° C. for about 24 hours.The atorvastatin hemi-calcium Form V obtained in this manner is of highpurity. However, it may be further purified by suspending in a mixtureof about 10% water and about 90% ethanol and recovering Form V from themixture in greater purity.

Amorphous atorvastatin hemi-calcium may be prepared by treating anyother form of atorvastatin hemi-calcium with acetone at room temperatureto reflux temperature for between a few hours and 25 hours, preferablyabout 16 hours. A preferred starting material is Form V.

Amorphous atorvastatin hemi-calcium also may be prepared by sonicatingany form of atorvastatin hemi-calcium in acetonitrile at any temperaturebetween room temperature and the reflux temperature of acetonitrile.Sonicating for a few minutes, preferably from 1 to 3 minutes, issufficient to transform the starting material into amorphousatorvastatin hemi-calcium. Preferred starting forms of atorvastatinhemi-calcium are Forms VII and I.

Amorphous atorvastatin hemi-calcium also may be prepared by ball millingof any crystalline form of atorvastatin hemi-calcium.

Atorvastatin hemi-calcium Forms VI, VII, VIII, IX, IXa, X, XI, XII, XIV,XVI and XVII are useful for reducing the plasma low density lipoproteinlevel of a patient suffering from or susceptible tohypercholesterolemia. For this purpose, it will typically beadministered to human patients in a unit dose of from about 0.5 mg toabout 100 mg. For most patients, a dose of from about 2.5 to about 80 mgper day, more particularly from about 2.5 to about 20 mg per day, causesa lowering of the plasma low density lipoprotein level in humanpatients. Whether such lowering is sufficient or whether the dose ordose frequency should be increased is a determination that is within theskill level of appropriately trained medical personnel.

A further aspect of the present invention is a pharmaceuticalcomposition and dosage form containing the novel forms of atorvastatinhemi-calcium.

The compositions of the invention include powders, granulates,aggregates and other solid compositions comprising novel Forms VI, VII,VIII, IX, IXa, X, XI, XII, XIV, XVI and XVII of atorvastatinhemi-calcium. In addition, Forms VI, VII, VIII, IX, IXa, X, XI, XII,XIV, XVI and XVII solid compositions that are contemplated by thepresent invention may further include diluents, such ascellulose-derived materials like powdered cellulose, microcrystallinecellulose, microfine cellulose, methyl cellulose, ethyl cellulose,hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, carboxymethyl cellulose salts and other substituted andunsubstituted celluloses; starch; pregelatinized starch; inorganicdiluents like calcium carbonate and calcium diphosphate and otherdiluents known to the pharmaceutical industry. Yet other suitablediluents include waxes, sugars and sugar alcohols like mannitol andsorbitol, acrylate polymers and copolymers, as well as pectin, dextrinand gelatin.

Further excipients that are within the contemplation of the presentinvention include binders, such as acacia gum, pregelatinized starch,sodium alginate, glucose and other binders used in wet and drygranulation and direct compression tableting processes. Excipients thatalso may be present in a solid composition of Forms VI, VII, VIII, IX,IXa, X, XI, XII, XIV, XVI and XVII atorvastatin hemi-calcium furtherinclude disintegrants like sodium starch glycolate, crospovidone,low-substituted hydroxypropyl cellulose and others. In addition,excipients may include tableting lubricants like magnesium and calciumstearate and sodium stearyl fumarate; flavorings; sweeteners;preservatives; pharmaceutically acceptable dyes and glidants such assilicon dioxide.

The dosages include dosages suitable for oral, buccal, rectal,parenteral (including subcutaneous, intramuscular, and intravenous),inhalant and ophthalmic administration. Although the most suitable routein any given case will depend on the nature and severity of thecondition being treated, the most preferred route of the presentinvention is oral. The Dosages may be conveniently presented in unitdosage form and prepared by any of the methods well-known in the art ofpharmacy.

Dosage forms include solid dosage forms, like tablets, powders,capsules, suppositories, sachets, troches and losenges as well as liquidsuspensions and elixirs. While the description is not intended to belimiting, the invention is also not intended to pertain to truesolutions of atorvastatin hemi-calcium whereupon the properties thatdistinguish the solid forms of atorvastatin hemi-calcium are lost.However, the use of the novel forms to prepare such solutions (e.g. soas to deliver, in addition to atorvastatin, a solvate to said solutionin a certain ratio with a solvate) is considered to be within thecontemplation of the invention.

Capsule dosages, of course, will contain the solid composition within acapsule which may be made of gelatin or other conventional encapsulatingmaterial. Tablets and powders may be coated. Tablets and powders may becoated with an enteric coating. The enteric coated powder forms may havecoatings comprising phthalic acid cellulose acetate,hydroxypropylmethyl-cellulose phthalate, polyvinyl alcohol phthalate,carboxymethylethylcellulose, a copolymer of styrene and maleic acid, acopolymer of methacrylic acid and methyl methacrylate, and likematerials, and if desired, they may be employed with suitableplasticizers and/or extending agents. A coated tablet may have a coatingon the surface of the tablet or may be a tablet comprising a powder orgranules with an enteric-coating.

Preferred unit dosages of the pharmaceutical compositions of thisinvention typically contain from 0.5 to 100 mg of the novel atorvastatinhemi-calcium Forms VI, VII, VIII, IX, IXa, X, XI, XII, XIV, XVI and XVIIor mixtures thereof with each other or other forms of atorvastatinhemi-calcium. More usually, the combined weight of the atorvastatinhemi-calcium forms of a unit dosage are from 2.5 mg. to 80 mg.

Having thus described the various aspects of the present invention, thefollowing examples are provided to illustrate specific embodiments ofthe present invention. They are not intended to be limiting in any way.

EXAMPLES General

Absolute ethanol containing less than 0.2% water was purchased fromBiolab®. Other reagents were reagent grade and were used as received.

Ball milling was performed using a Retsch centrifugal ball-mill S— 100equipped with a 250 ml stainless steal milling chamber and twenty seven10 mm diameter stainless steal balls as milling media.

Preparation of Atorvastatin Hemi-Calcium Form VI Example 1

Atorvastatin hemi-calcium Form I (1 g) was dissolved in acetone (9 ml)at room temperature and stirred for 2.5 hours. Then, water (8.5 ml) wasadded to get a precipitation and the mixture was then stirred foranother 2.5 hours. The white solid was then filtered and dried at 50° C.for 5 hrs to obtain atorvastatin hemi-calcium Form VI (0.88 g, 88%).

Preparation of Atorvastatin Hemi-Calcium Form VII Example 2

Atorvastatin hemi-calcium Form V (1.00 g) was stirred in absolute EtOH(400 ml) at room temperature for 16 h. The solid was collected byfiltration and dried at 65° C. for 24 h to give atorvastatinhemi-calcium Form VII (40 mg, 40%).

Example 3

Atorvastatin hemi-calcium Form I (75 mg) was stirred in absolute EtOH(30 ml) at room temperature for 16 h. The solid was collected byfiltration and dried at 65° C. for 24 h to give atorvastatinhemi-calcium Form VII (0.60 g, 80%).

Preparation of Atorvastatin Hemi-Calcium Form VIII Example 4

To a flask equipped with a magnetic stirrer 1.0 g (1.59×10⁻³ mole) of[R—(R*,R*)]-2-(4-fluorophenyl)-β,δ-dioxane-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-tert-butylheptanoicester were put in suspension in a 90% aqueous solution of acetic acid(10 ml). The reaction mixture was heated to 50° C. for three hours andthen stirred at room temperature until the reaction was complete asdetermined by HPLC. The solvent was evaporated and the traces of aceticacid were removed by azeotropic distillation with toluene (3×100 ml) toobtain an oil with some toluene. This oil was dissolved in EtOH (10 ml)and water (2 ml). Then 5.5 eq (8.4×10⁻³ mole, 622 mg) of Ca(OH)₂ andtetrabutyl ammonium bromide (5%, 0.05 g) were added. The reactionmixture was heated at 50° C. for 5 hours until the reaction was completeaccording to HPLC. Then a hot filtration was done under vacuum to removethe excess of Ca(OH)₂. The reaction mixture was then cooled to roomtemperature. To this solution water (50 ml) was added while stirring.The white precipitate was stirred at RT overnight, filtered under vacuumand dried at 65° C. for 18 hours to give 145 mg (16%) of atorvastatinhemi-calcium salt Form VIII.

Example 5

Atorvastatin hemi-calcium Form I (1 g) was slurried in absolute EtOH (80ml), under reflux, for 24 hrs. The white solid was then filtered anddried at 65° C. for 20 hrs to obtain atorvastatin hemi-calcium Form VIII(0.85 g, 85%).

Example 6

Atorvastatin hemi-calcium Form I (1 g) was poured in boiling absoluteEtOH (40 ml). The compound began first to get soluble and thenprecipitate again. To this mixture was added MeOH (20 ml). The whitesolid was then filtered and dried at 50° C. for 20 hrs in a vacuum ovento obtain atorvastatin hemi-calcium Form VIII (188 mg, 19%).

Example 7

A suspension of 1.0 g of Atorvastatin hemi-calcium salt Form V in1-butanol (4 ml) and H₂O (16 ml) was heated to reflux temperature for 1hr. The mixture was then cooled to room temperature and stirred at thistemperature for additional 16 hrs. The solid was filtered and dried at50° C. in a vacuum oven for 16 hrs to give 0.9 g (91%) of Atorvastatinhemi-calcium salt Form VIII.

Example 8

5.0 g of Atorvastatin hemi-calcium salt Form V were added to a boiledsolution of Ethanol 96% (150 ml). The mixture was refluxed for 2.5 hrs.Then it was cooled to 20° C. during 1.5 hrs, and stirred at thistemperature for additional 16 hrs. The solid was filtered, washed withEthanol 96% (2×25 ml) and dried at 65° C. for 20 hrs to give 4.4 g (88%)of Atorvastatin hemi-calcium salt Form VIII. During this processchemical purification occurs, so this process is good also forpurification.

Example 9

5.0 g of Atorvastatin hemi calcium salt Form V, with a level of 0.12% ofDes-fluoro Atorvastatin, were added to a boiled solution of Ethanol 96%(150 ml). The mixture was refluxed for 2.5 hrs. Then it was cooled to20° C. during 1.5 hrs and stirred at this temperature for additional 16hrs. The solid was filtered, washed with Ethanol 96% (2×25 ml) and driedat 65° C. for 20 hrs to give 4.4 g (88%) of Atorvastatin hemi calciumsalt with a level of 0.06% of Des-fluoro Atorvastatin. Atorvastatin isobtained in Form VIII by this procedure.

Example 10

Atorvastatin hemi-calcium Form V (5 g) in absolute ETOH (35 ml) wasrefluxed for 2.5 h. The reaction mixture was then cooled to roomtemperature and stirred for an additional 16 h. Absolute ethanol (15 ml)was then added and the suspension was filtered and the collected solidswere dried at 65° C. for 20 h to yield-atorvastatin hemi-calcium FormVIII (4.7 g, 94%).

Preparation of Atorvastatin Hemi-Calcium Form IX Example 11

Atorvastatin hemi-calcium Form I (1 g) was slurried in 1-butanol (20 ml)under reflux for 30 minutes. The mixture was then cooled to roomtemperature. The white solid was then filtered and dried at 50° C. undervacuum for 20 hrs to yield atorvastatin hemi-calcium Form IX (0.94 g,94%). KF=0.9.

Example 12

Atorvastatin hemi-calcium Form I (1 g) was slurried in 1-butanol (20 ml)under reflux for 30 minute. Then n-hexane (40 ml) was added for furtherprecipitation and the reaction mixture was stirred at room temperaturefor 2 hours. The white solid was then filtered and dried at 50° C. in avacuum oven for 20 hrs to yield atorvastatin Form IX (0.96 g, 96%).

Example 13

Atorvastatin hemi-calcium Form I (1 g) was slurried in 1-butanol (20 ml)under reflux for 30 minute. Then, IPA (40 ml) was added for furtherprecipitation and the reaction mixture was stirred at room temperaturefor 2 hours. The white solid was then filtered and dried at 50° C. for20 hrs in a vacuum oven to yield atorvastatin hemi-calcium Form IX (0.94g, 94%) containing 0.9% water by Karl Fisher analysis.

Example 14

Atorvastatin hemi-calcium Form VIII (800 mg) was stirred in absoluteEtOH (320 ml) at room temperature for 16 h. The solid was collected byfiltration and dried at 65° C. for 24 hours to give atorvastatinhemi-calcium Form IX (630 mg, 79%).

Example 15

A mixture of atorvastatin hemi-calcium Form V (2.00 g) and 1-butanol (40ml) was refluxed at 118° C. for half an hour. The mixture was thencooled to room temperature and stirred for an additional 3-hours. Thesolid was then collected by filtration and dried at 65° C. for 24 hoursto give atorvastatin hemi-calcium Form IX (1.83 g, 92%).

Example 16

Atorvastatin hemi-calcium Form VIII was stored under 100% relativehumidity at room temperature for nine days. The resulting solid wasidentified as Form IX by powder X-ray diffraction analysis.

Example 17

Atorvastatin hemi-calcium salt Form V (1 g) in 1-BuOH (10 ml) and H₂O(10 ml) was heated to reflux for 1 h. The mixture was then cooled toroom temperature and stirred at this temperature for additional 16 hrs.Filtration and drying at 65° C. for 24 hrs gave 0.79 g (79%) ofAtorvastatin hemi-calcium salt form IX.

Example 18

Atorvastatin hemi-calcium salt Form V (1 g) in 1-BuOH (10 ml) and EtOH(10 ml) was heated to reflux for 1 h. The mixture was then cooled toroom temperature and stirred at this temperature for additional 16 hrs.Filtration and drying at 65° C. for 24 hrs gave 0.98 g (98%) ofAtorvastatin. hemi-calcium salt form IX.

Example 19

Atorvastatin hemi-calcium salt Form V (5 g) was suspended in a mixtureof 1-butanol (70 ml) and water (30 ml) at reflux temperature (87° C.)for 17.5 hours. The mixture was then cooled to room temperature and thento 0° C. using an ice-bath. The product was isolated by filtration anddried at 65° C. in a vacuum oven for 24 hours to give 0.95 g (19%) ofAtorvastatin hemi-calcium salt Form IX.

Example 20

Atorvastatin hemi-calcium salt Form V (5 g) was suspended in a mixtureof 1-butanol (60 ml) and water (40 ml) at reflux temperature (90.5° C.)for 15 hours. The mixture was then cooled to room temperature and thento 0° C. using an ice-bath. The product was isolated by filtration anddried at 65° C. in a vacuum oven for 24 hours to give 2.1 g (41%) ofAtorvastatin hemi-calcium salt Form IX.

Example 21

Atorvastatin hemi-calcium salt Form V (S g) was suspended in a mixtureof 1-butanol (50 ml) and water (50 ml) at reflux temperature (91° C.)for 15 hours. The mixture was then cooled to room temperature and thento 0° C. using an ice-bath. The product was isolated by filtration anddried at 65° C. in a vacuum oven for 24 hours to give 2.9 g (58%) ofAtorvastatin hemi-calcium salt Form IX.

Example 22

Atorvastatin hemi-calcium salt Form V (3.9 g) was suspended in a mixtureof 1-butanol (20 ml) and water (80 ml) at reflux temperature (91° C.)for 16.5 hours. The mixture was then cooled to room temperature and thento 0° C. using an ice-bath. The product was isolated by filtration anddried at 65° C. in a vacuum oven for 24 hours to give 3.4 g (86%) ofAtorvastatin hemi-calcium salt Form IX.

Example 23

Atorvastatin hemi-calcium salt Form V (5 g) was suspended in a mixtureof 1-butanol (50 ml) and Acetone (50 ml) at reflux temperature (71° C.)for 17 hours. The mixture was then cooled to room temperature and thento 0° C. using an ice-bath. The product was isolated by filtration anddried at 65° C. in a vacuum oven for 24 hours to give 4.6 g (93%) ofAtorvastatin hemi-calcium salt Form IX.

Example 24

Atorvastatin hemi-calcium salt Form V (5 g) was suspended in a mixtureof 1-butanol (50 ml) and IPA (50 ml) at reflux temperature (91.5° C.)for 15 hours. The mixture was then cooled to room temperature and thento 0° C. using an ice-bath. The product was isolated by filtration anddried at 65° C. in a vacuum oven for 24 hours to give 4.7 g (94%) ofAtorvastatin hemi-calcium salt Form IX.

Example 25

Atorvastatin hemi-calcium salt Form V (5 g) was suspended in a mixtureof 1-butanol (50 ml) and THF (50 ml) at reflux temperature (80° C.) for15 hours. The mixture was then cooled to room temperature and then to 0°C. using an ice-bath. The product was isolated by filtration and driedat 65° C. in a vacuum oven for 24 hours to give 2.4 g (48%) ofAtorvastatin hemi-calcium salt Form IX.

Example 26

Atorvastatin hemi-calcium salt Form V (5 g) was suspended in a mixtureof 1-butanol (50 ml) and 1-propanol (50 ml) at reflux temperature (95°C.) for 16 hours. The mixture was then cooled to room temperature andthen to 0° C. using an ice-bath. The product was isolated by filtrationand dried at 65° C. in a vacuum oven for 24 hours to give 4.8 g (96%) ofAtorvastatin hemi-calcium salt Form IX.

Example 27

Atorvastatin hemi-calcium salt Form V (5 g) was suspended in a mixtureof 1-butanol (50 ml) and MTBE (50 ml) at reflux temperature (73° C.) for16 hours. The mixture was then cooled to room temperature and then to 0°C. using an ice-bath. The product was isolated by filtration and driedat 65° C. in a vacuum oven for 24 hours to give 4.8 g (97%) ofAtorvastatin hemi-calcium salt Form IX.

Preparation of Atorvastatin Hemi-Calcium Form IXa Example 28

Atorvastatin hemi-calcium salt Form V (5 g) was suspended in a mixtureof 1-butanol (90 ml) and water (10 ml) at reflux temperature (85° C.)for 16 hours. The mixture was then cooled to room temperature and thento 0° C. using an ice-bath. The product was isolated by filtration anddried at 65° C. in a vacuum oven for 24 hours to give 4.73 g (95%) ofAtorvastatin hemi-calcium crystalline Form IXa.

Example 29

Atorvastatin hemi-calcium salt Form V (5 g) was suspended in a mixtureof 1-butanol (10 ml) and water (90 ml) at reflux temperature for 16hours. The mixture was then cooled to room temperature and then to 0° C.using an ice-bath. The product was isolated by filtration and dried at65° C. in a vacuum oven for 24 hours to give atorvastatin hemi-calciumcrystalline Form IXa.

Preparation of Atorvastatin Hemi-Calcium Form X Example 30

Atorvastatin hemi-calcium Form V (10.00 g) was suspended in a mixture ofEtOH (135 ml) and water (24 ml) and heated to reflux for 1 h. Themixture was then cooled to room temperature and stirred for an addition16 h. The solid was collected by filtration and dried at 65° C. for 24 hto give atorvastatin hemi-calcium Form X (8.26 g, 83%).

Example 31

Atorvastatin hemi-calcium Form V (1.00 g) in a mixture of EtOH (9 ml)and water (1.6 ml) was refluxed for 1 h. The mixture was cooled to roomtemperature and then stirred an additional 3 h. The solid was collectedby filtration and dried at 65° C. for 24 h to give atorvastatinhemi-calcium Form X (0.80 g, 80%).

Preparation of Atorvastatin Hemi-Calcium Form XI Example 32

1.0 g of Atorvastatin hemi-calcium salt Form V was stirred inMethylethyl ketone (“MEK”) (5 ml) at room temperature for 24 hrs. Thesolid was then filtered, washed with MEK (2 ml) and dried at 65° C. for20 hrs to give 0.5 g (50%) of Atorvastatin hemi-calcium salt Form XI.

Example 33

A suspension of 1.0 g of Atorvastatin hemi-calcium salt Form V inIso-propyl alcohol (“IPA”) (7 ml) was heated to reflux temperature for 1hr. The mixture was then cooled to room temperature and stirred at thistemperature for additional 20 hrs. A gelatinous product was obtained.After addition of IPA (3 ml) the gel was filtered and dried at 65° C.for 20 hrs to give 0.8 g (80%) of Atorvastatin hemi-calcium salt FormXI.

Preparation of Atorvastatin Hemi-Calcium Form XII Example 34

To a cylindrical reactor equipped with a distillation apparatus and amechanical stirrer, 20 g (30.6 mmole) of[R—(R*,R*)]-2&4-fluorophenyl)-β,δ-dioxane-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-tert-butylheptanoicester (=pyrrole acetonide ester=PAE) were put in suspension in 250 ml ofabsolute Ethanol and 50 ml of aqueous 1.5% Hydrochloric acid. Thereaction mixture was heated to 40° C. for 9-11 hrs, while a continuousdistillation of a mixture of Ethanol, Acetone and water, under reducedpressure (500-600 mbar), was performed. Make-up of absolute Ethanol wasdone every hour (35-40 ml.). After 9-11 hours there was a reduction inthe level of PAE to below 0.1% (according to HPLC). Without any furthertreatment, Ca(OH)₂ (1.5 eq., 3.4 g) were added. The reaction mixture washeated to 70° C. for 4-5 hrs. Then the excess of Ca(OH)₂ was collectedby filtration. To the hot filtrate (65° C.), 350 ml of water were addedslowly (using a dosing pump) during 3/4-1 hour at 65° C. During theaddition of water Atorvastatin hemi-calcium salt precipitated. After theaddition of water the reaction mixture was heated to reflux (84° C.)till a clear solution was obtained. Then the mixture was cooled to 20°C. during 3 hrs and was stirred at this temperature for an additional12-16 hrs. The solid was then filtered to give 45.0 g of wet cake ofAtorvastatin hemi-calcium salt crystal form XII.

Preparation of Atorvastatin Hemi-Calcium Form XIV Example 35

Atorvastatin hemi-calcium Form V (1 g) was introduced into a 500 mlbeaker. Water (240 ml) was added. The suspension was mixed for 5 hours.A fine suspension appeared. It was left standing undisturbed for threedays. After three days white flakes formed in the suspension. Thesuspension was then filtered and analyzed by XRD as is. The resultingform is novel atorvastatin hemi-calcium Form XIV.

Preparation of Atorvastatin Hemi-Calcium Form XVI Example 36

A small aliquot of form XIV was exposed to the air at room temperaturefor three hours, and then analyzed by XRD. The resulting form is FormXVI.

Preparation of Atorvastatin Hemi-Calcium Form XVII Example 37

Wet Atoravstatin hemi-calcium salt Form V (53 g) was added to a hotsolution (about 70° C.) of ethanol (about 485 ml). The resultingquantity of water in ethanol should be about 4%. The mixture wasrefluxed for about 2 hours. The mixture was cooled to 15-20 degrees. Thesolid was filtered, washed with ethanol 96%. The material was thenanalysed by X-Ray powder diffraction and found to contain Form XVI.Conventional drying (40-70) degrees produced atorvastatin hemi-calciumForm VIII.

Example 38

About 20 kg of Atorvastatin hemi-calcium Form V was added to a hotsolution (about 70° C.) of ethanol (about 600 liters). The resultingquantity of water in ethanol should be about 4%, and it is adjustedaccording to the initial moisture level of Form V. The mixture wasrefluxed for about 2.5 hours. The mixture was cooled to 15-20° C. andstirred at this temperature for at least 3 hours. The solid wasfiltered, washed with 96% ethanol. The material was then analyzed bypowder X-Ray diffraction and found to contain form XVII. Conventionaldrying at 40-70° C. produced atorvastatin hemi-calcium form VIII.

Preparation of Known Atorvastatin Hemi-Calcium Form I Example 39

Atorvastatin hemi-calcium Form V (1.00 g) was stirred in water (400 ml)at room temperature for 16 h. The solid was collected by filtration anddried at 65° C. for 24 hours to yield atorvastatin hemi-calcium Form I(0.7 g, 70%).

Example 40

A mixture of atorvastatin hemi-calcium Form VII (10.00 g) in water (100ml) was refluxed for 2 h. The mixture was cooled to room temperature andstirred for an additional hour. The solid was collected by filtrationand dried at 65° C. for 24 h to yield atorvastatin hemi-calcium Form I(9.64 g, 96%).

Example 41

Atorvastatin hemi-calcium Form VIII (800 mg) was stirred in water (320ml) at room temperature for 16 h. The solid was collected by filtrationand dried at 65° C. for 24 h to yield atorvastatin hemi-calcium Form I(350 mg, 44%).

Example 42

Atorvastatin hemi-calcium Form X (1.0 g) was stirred in water (400 ml)at room temperature for 24 h. The solid was collected by filtration anddried at 65° C. for 24 h to yield atorvastatin hemi-calcium Form I (720mg, 72%).

Example 43

Atorvastatin hemi-calcium Form IX (750 mg) was stirred in water (300 ml)at room temperature for 24 h. The solid was collected and dried at 65°C. for 20 h to give atorvastatin calcium Form I (420 mg, 56%).

Example 44

Atorvastatin hemi-calcium Form VII (1.00 g) was stirred in absolute EtOH(20 ml) at room temperature. The slurry was then placed into a sonicatorfor 1.5 min (energy=235 kJ, Amp.=50%) to obtain a clear solution. Afteraddition of water (14 ml), a precipitate formed and the slurry was putin the sonicator for another 2 min. (energy=3.16 kJ, Amp.=50%) whichcaused the slurry to gel The gel was dried at 65° C. for 20 h to giveatorvastatin hemi-calcium Form I (0.50 g, 50%).

Example 45

Atorvastatin hemi-calcium Form VII (1.00 g) was stirred in water (200ml) at room temperature. The slurry was then placed into a sonicator for2 min. (energy=3.0 kJ, Amp.=50%) which caused the slurry to gel. The gelwas dried at 65° C. for 20 h to yield atorvastatin hemi-calcium Form I(0.92 g, 92%).

Preparation of Known Atorvastatin Hemi-Calcium Form II Example 46

To a cylindrical reactor equipped with a distillation apparatus and amechanical stirrer, 20 g (30.6 mmole) of[R—(R*,R*)]-2-(4-fluorophenyl)-β,δ-dioxane-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-tert-butylheptanoicester (=pyrrole acetonide ester=PAE) were put in suspension in 135 ml ofMethanol and 7.6 ml of aqueous 10% Hydrochloric acid. The reactionmixture was heated to 35° C. for 3 hrs, while a continuous distillationof a mixture of Methanol, Acetone and water under reduced pressure (820mbar) was performed. Make-up of Methanol was done every ½ hour (35 ml).After 3 hrs the level of PAE reduced below 0.1% (according to HPLC).Without any further treatment, Ca(OH)₂ (1.5 eq., 3.4 g), water (5 ml)and Methanol (45 ml) were added. The reaction mixture was heated to 70°C. for 2 hrs. Then the excess of Ca(OH)₂ was collected by filtration andthe Ca(OH)₂ cake was washed with Methanol (2×10 ml). To the filtrate,300 ml of water were added slowly (using a dosing pump) during ¾ hour at65° C. During the addition of water Atorvastatin hemi-calcium saltprecipitated. After the addition of water the reaction mixture washeated to reflux temperature (78° C.) for ½ hour. Then the mixture wascooled to 20° C. during 3 hrs and was stirred at this temperature foradditional 20 hrs. The solid was then filtered and dried at 65° C. for48 hrs to give 16.9 g (96%) Atorvastatin hemi-calcium salt crystal formII.

KF=3.2% Preparation of Known Atorvastatin Hemi-Calcium Form IV Example47

Atorvastatin hemi-calcium salt Form I (1.0 g) was stirred in 9 ml of1-butanol at room temperature for 24 hours. The white solid was thenfiltered and dried at 50° C. in a vacuum oven for 16 hours to obtain0.83 g (83%) of atorvastatin hemi-calcium salt Form IV.

Example 48

Atorvastatin hemi-calcium salt Form V (1.0 g) was stirred in 20 ml of1-butanol at room temperature for 72 hours. The white solid was thenfiltered and dried at 65° C. in an oven for 20 hours to obtain 0.82 g(82%) of atorvastatin hemi-calcium salt Form IV.

Example 49

Atorvastatin hemi-calcium salt form V (2.0 g) was stirred in a mixtureof EtOH (18 ml) and water (3.2 ml) at 50° C. for 1 hour. The precipitatewas then filtered and dried at 65° C. for 20 hours to obtain 1.60 g(80%) of atorvastatin hemi-calcium salt form IV.

Example 50

A mixture of atorvastatin hemi-calcium Form V (2.00 g) and methanol (20ml) was refluxed for 1 hour. The mixture was cooled to room temperatureand stirred for an additional 16 hours. The solid was collected byfiltration and dried at 65° C. for 24 to give atorvastatin calcium FormIV (1.37 g, 56%).

Example 51

A mixture of atorvastatin hemi-calcium Form V (1.00 g) in methanol (10ml) was stirred at room temperature for 20 hours. The solid wascollected by filtration and dried at 65° C. for 24 hours to giveatorvastatin hemi-calcium Form IV (0.25 g, 25%).

Preparation of Atorvastatin Hemi-Calcium Form V Example 52

To a cylindrical reactor equipped with a distillation apparatus and amechanical stirrer, 20 g (30.6 mmole) of[R—(R*,R*)]-2-(4-fluorophenyl)-β,δ-dioxane-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-tert-butylheptanoicester (=pyrrole acetonide ester=PAE) were put in suspension in 250 ml ofabsolute Ethanol and 50 ml of aqueous 1.5% Hydrochloric acid. Thereaction mixture was heated to 40° C. for 9-11 hrs, while a continuousdistillation of a mixture of Ethanol, Acetone and water, under reducedpressure (500-600 mbar), was performed. Make-up of absolute Ethanol wasdone every hour (35-40 ml.). After 9-11 hours there was a reduction inthe level of PAE to below 0.1% (according to HPLC). Without any furthertreatment, Ca(OH)₂ (1.5 eq., 3.4 g) were added. The reaction mixture washeated to 70° C. for 4-5 hrs. Then the excess of Ca(OH)₂ was collectedby filtration. To the hot filtrate (65° C.), 350 ml of water were addedslowly (using a dosing pump) during ¾-1 hour at 65° C. During theaddition of water Atorvastatin hemi-calcium salt precipitated. After theaddition of water the reaction mixture was heated to reflux (84° C.)till a clear solution was obtained. Then the mixture was cooled to 20°C. during 3 hrs and was stirred at this temperature for an additional 20hrs. The solid was then filtered to give 45.0 g of wet cake ofAtorvastatin hemi-calcium salt crystal form XII. This solid was dried at65° C. for 24 hrs to give 16.7 g (95%) Atorvastatin hemi-calcium saltcrystal form V.

KF=2.8%-6.6%. Process for Purifying Atorvastatin Hemi-calcium Form VExample 53

5.0 g of Atorvastatin hemi-calcium salt Form V were added to a boiledaqueous solution of Ethanol 90% (150 ml). The mixture was refluxed for2.5 hrs. Then it was cooled to 20° C. during 1.5 hrs and stirred at thistemperature for additional 16 hrs. The solid was then filtered, washedwith Ethanol 90% (2×25 ml) and dried at 65° C. for 20 hrs to give 3.4 g(68%) of Atorvastatin hemi-calcium salt Form V.

Preparation of Known Amorphous Atorvastatin Hemi-Calcium Example 54

Atorvastatin hemi-calcium Form V (2.00 g) was stirred in acetone (14 ml)at room temperature in a closed flask for 16 h. After 2 hours, themixture clarified. While continuing to stir at room temperature, a solidprecipitated. The acetone was decanted and the solid was collected witha spatula and transferred to a drying oven and dried at 65° C. for 20 hto give amorphous atorvastatin hemi-calcium (1.85 g, 93%).

Example 55

Atorvastatin hemi-calcium Form VII (1.00 g) was stirred in acetonitrile(20 ml) at room temperature. The slurry was then sonicated for 2 min.(energy=2.5 kJ, Amp.=50%). After decantation the acetonitrile, the solidwas dried at 65° C. for 20 h to give amorphous atorvastatin hemi-calcium(0.71 g, 71%).

Example 56

Atorvastatin hemi-calcium Form I (1.00 g) was stirred in acetonitrile(20 ml) at room temperature. The slurry was then placed into a sonicatorfor 2 min. (energy=2.5 kJ, Amp.=50%). After decanting the acetonitrile,the solid was dried at 65° C. for 20 h to give amorphous atorvastatinhemi-calcium (0.71 g, 71%).

Example 57

Atorvastatin hemi-calcium (108 g) and twenty seven 10 mm diameterstainless steel milling balls were loaded into the milling chamber ofthe ball mill. The chamber was weighed and the mill was balancedaccording to the weight. The mill was operated at 500 rpm with themill's reversing system on for 0.5 hr. The build-up material was scrapedfrom the chamber walls into the bulk, and the mill was again operatedfor 4 hr, with cleaning of build-up every 15 min. finally, the materialwas separated from the balls by sieving with 300 μm screen. Theresulting material was analyzed by PXRD and found to be amorphous. Theprocess was repeated using atorvastatin Forms I, V and VIII and in eachinstance amorphous atorvastatin hemi-calcium was obtained.

Example 58

Atorvastatin hemi-calcium Form V (5.0 g) was suspended in a mixture of1-butanol (30 ml) and water (70 ml) at reflux temperature (91° C.) for12.5 hours. The mixture was then cooled to room temperature and then to0° C. using an ice-bath. The product was isolated by filtration anddried at 65° C. in a vacuum oven for 24 hours to give 2.5 g (51%) ofamorphous Atorvastatin hemi-calcium salt.

Having thus described the invention with reference to particularpreferred embodiments and illustrated it with examples, those in the artmay appreciate modifications to the invention as described andillustrated that do not depart from the spirit and scope of theinvention as defined by the claims which follow.

1. Solid crystalline atorvastatin hemi-calcium and solvates thereofcharacterized by a powder X-ray diffraction pattern generated usingCuK_(α) radiation substantially as depicted in FIG.
 6. 2. Solidcrystalline atorvastatin hemi-calcium and solvates thereof characterizedby a reproducible physical or spectroscopic analysis result selectedfrom the group consisting of: a) a powder X-ray diffraction patterngenerated using CuK_(α) radiation with peaks at 19.1, 19.9, 21.4, 22.5,23.5±0.2 degrees two-theta; b) d-spacings of about 30.86, 18.67, 16.91,15.17, 12.66, 11.20, 9.50, 9.28, 8.63, 7.69, 7.38, 6.51, 5.45, 5.26,5.20, 5.12, 4.87, 4.76; 4.63, 4.47, 4.14, 4.08, 3.78, 3.73, 3.62, and3.58 Å; c) a monoclinic unit cell with cell parameters: a=18.75-18.85 Å,b=5.525-5.54 Å, c=30.9-31.15 Å and β=96.5 to 97.5°; d) a solid statecross-polarization/magic angle spinning ¹³C nuclear magnetic resonancespectrum with resonances at 24.9, 26.1, 119.5, 120.2, 121.7, 122.8,126.7, 128.6, 129.4, 134.3, 135.1, 136.8, 138.3 and 139.4 parts permillion; and e) a solid state cross-polarization/magic angle spinning¹³C nuclear magnetic resonance spectrum wherein the chemical shiftdifferences between the lowest resonance and other resonances are: 2.4,6.9, 8.1, 22.4, 28.4, 53.0, 55.4, 96.3, 98.0, 101.5, 102.2, 103.7,104.8, 108.7, 110.6, 111.4, 116.3, 117.1, 118.8, 120.3, 121.4, 141.9,148.3, 160.4 and 168.6 parts per million.
 3. The solid crystallineatorvastatin hemi-calcium and solvates thereof of claim 2 wherein theresult is the powder X-ray diffraction pattern having peaks at 19.1,19.9, 21.4, 22.5, 23.5±0.2 degrees two-theta and the powder X-raydiffraction pattern further includes peaks at 6.9, 17.0, 17.4, 18.2,18.6±0.2 degrees two-theta.
 4. The solid crystalline atorvastatinhemi-calcium and solvates thereof of claim 2 wherein the result is thed-spacings and Form IX is further characterized by a high resolutionX-ray powder diffraction pattern substantially as shown in FIG. 7 whenirradiated with X-rays with a wavelength of about 1.15 Å.
 5. The solidcrystalline atorvastatin hemi-calcium and solvates thereof of claim 2wherein the result is a solid state cross-polarization/magic anglespinning ¹³C nuclear magnetic resonance spectrum with resonances at24.9, 26.1, 119.5, 120.2, 121.7, 122.8, 126.7, 128.6, 129.4, 134.3,135.1, 136.8, 138.3 and 139.4 parts per million and the spectrum furtherincludes resonances at 18.0, 20.4, 40.4, 46.4, 71.0, 73.4, 114.3, 116.0,159.9, 166.3, 178.4 and 186.6 parts per million.
 6. The solidcrystalline atorvastatin hemi-calcium and solvates thereof of claim 2wherein the result is a solid state cross-polarization/magic anglespinning ¹³C nuclear magnetic resonance spectrum with resonances at24.9, 26.1, 119.5, 120.2, 121.7, 122.8, 126.7, 128.6, 129.4, 134.3,135.1, 136.8, 138.3 and 139.4 parts per million and the spectrum issubstantially as depicted FIG.
 8. 7. The solid crystalline atorvastatinhemi-calcium and solvates thereof of claim 2 containing up to 7% water.8. The solid crystalline atorvastatin hemi-calcium and solvates thereofof claim 2 containing from about one to about four moles of water. 9.The solid crystalline atorvastatin hemi-calcium and solvates thereof ofclaim 2 that is a butanolate.
 10. The solid crystalline atorvastatinhemi-calcium butanolate of claim 9 containing up to about 5% butanol.11. The solid crystalline atorvastatin hemi-calcium and solvates thereofof claim 2 having a narrow particle size distribution.
 12. The solidcrystalline atorvastatin hemi-calcium and solvates thereof of claim 11wherein all of the particles are 100 microns or less in diameter. 13.The solid crystalline atorvastatin hemi-calcium and solvates thereof ofclaim 12 wherein all of the particles are 50 microns or less indiameter.
 14. A process for preparing solid crystalline atorvastatinhemi-calcium having at least one characteristic of Form IX comprisingthe steps of: a) suspending any other crystalline or amorphous form ofatorvastatin hemi-calcium in 1-butanol for a period of time sufficientto convert the other form to Form IX and b) recovering solid crystallineatorvastatin hemi-calcium having at least one characteristic of Form IXfrom the suspension.
 15. The process of claim 14 wherein the other formis selected from the group consisting of Form I, Form V and Form XII.16. The process of claim 14 wherein the temperature of the suspension iselevated to the reflux temperature of 1-butanol before recovering solidcrystalline atorvastatin hemi-calcium having at least one characteristicof Form 1× from the suspension.
 17. The process of claim 14 furthercomprising the step of adding an anti-solvent to the suspension beforerecovering solid crystalline atorvastatin hemi-calcium having at leastone characteristic of Form IX.
 18. The process of claim 17 wherein theanti-solvent is selected from the group consisting of n-hexane,isopropanol and water.
 19. A process for preparing solid crystallineatorvastatin hemi-calcium having at least one characteristic of Form IXcomprising exposing atorvastatin hemi-calcium Form VIII to an atmosphereof from about 80% to about 100% relative humidity.
 20. The process ofclaim 19 wherein the Form VIII is exposed to the humid atmosphere forabout 9 days or less.
 21. The process of claim 19 wherein the Form VIIIis exposed to the humid atmosphere at room temperature.
 22. A processfor preparing solid crystalline atorvastatin hemi-calcium having atleast one characteristic of Form IX comprising the steps of: a)suspending Form VIII atorvastatin hemi-calcium in ethanol for a periodof time sufficient to convert the Form VIII into the solid crystallineatorvastatin hemi-calcium having at least one characteristic of Form IXand b) recovering the solid crystalline atorvastatin hemi-calcium havingat least one characteristic of Form IX from the suspension.
 23. Theprocess of claim 22 wherein the ethanol contains about 0.5% or lesswater.
 24. The process of claim 23 wherein the ethanol contains about0.2% or less water.
 25. The process of claim 22 wherein the temperatureof the suspension is maintained at about room temperature over the timeperiod in which the other form is converted into the solid crystallineatorvastatin hemi-calcium having at least one characteristic of Form IX.26. The process of claim 22 wherein the time period sufficient toconvert the other form into the solid crystalline atorvastatinhemi-calcium having at least one characteristic of Form IX is about 16hours.
 27. Solid crystalline atorvastatin hemi-calcium and solvatesthereof characterized by a powder X-ray diffraction pattern having peaksat 9.3 and 9.5±0.2 degrees two-theta.
 28. The solid crystallineatorvastatin hemi-calcium and solvates thereof of claim 27 furthercharacterized by peaks in the powder X-ray diffraction pattern at 15.7,20.5, 21.1, 22.8, 23.8, 24.0, 25.3, 26.4, 26.8, 27.2, 29.2 and 31.6degrees two-theta.
 29. The solid crystalline atorvastatin hemi-calciumand solvates thereof of claim 27 further characterized by a powder X-raydiffraction pattern generated using CuK_(α) radiation substantially asdepicted in FIG.
 9. 30. A process for preparing atorvastatinhemi-calcium having at least one characteristic of Form IXa comprisingthe steps of: a) suspending atorvastatin hemi-calcium Form V in amixture selected from the group consisting of mixtures from about 85% toabout 95% 1-butanol and from about 5% to about 15% water and mixtures offrom about 5% to about 15% 1-butanol and from about 85% to about 95%water for a period of time sufficient to convert Form V to theatorvastatin hemi-calcium having at least one characteristic of FormIXa, and b) recovering solid crystalline atorvastatin hemi-calciumhaving at least one characteristic of Form IXa from the suspension. 31.The process of claim 30 wherein the mixture is about 90% 1-butanol andabout 10% water on a volume basis.
 32. The process of claim 30 whereinthe mixture is about 10% 1-butanol and about 90% water on a volumebasis.
 33. The process of claim 30 wherein the mixture is present in anamount of at least about 20 milliliters per gram of atorvastatinhemi-calcium Form V.
 34. The process of claim 30 wherein the suspensionis heated to an elevated temperature before recovering the solidcrystalline atorvastatin hemi-calcium having at least one characteristicof Form IXa from the suspension.
 35. The process of claim 34 wherein theelevated temperature is about the reflux temperature of the mixture. 36.The process of claim 35 wherein the reflux temperature is about 85° C.37. The process of claim 30 wherein the time sufficient to convert FormV to the solid crystalline atorvastatin hemi-calcium having at least onecharacteristic of Form IXa is about 16 hours or less.
 38. The process ofclaim 30 wherein the Form V is impure and the solid crystallineatorvastatin hemi-calcium having at least one characteristic of Form IXais more pure than the Form V by about 50% or more.
 39. Solid crystallineatorvastatin hemi-calcium and solvates thereof having at least onecharacteristic of Form IXa prepared by a process comprising the stepsof: a) suspending atorvastatin hemi-calcium Form V in a mixture selectedfrom the group consisting of mixtures from about 85% to about 95%1-butanol and from about 5% to about 15% water and mixtures of fromabout 5% to about 15% 1-butanol and from about 85% to about 95% waterfor a period of time sufficient to convert Form V to the atorvastatinhemi-calcium having at least one characteristic of Form IXa, and b)recovering solid crystalline atorvastatin hemi-calcium having at leastone characteristic of Form IXa from the suspension.
 40. Solidcrystalline and highly pure atorvastatin hemi-calcium and solvatesthereof having at least one characteristic of Form IX prepared by aprocess comprising the steps of: a) suspending atorvastatin hemi-calciumForm V in a mixture of 90% 1-butanol and 10% water on a volume basis fora period of time sufficient to convert Form V to the atorvastatinhemi-calcium having at least one characteristic of Form IXa, and b)recovering solid crystalline atorvastatin hemi-calcium having at leastone characteristic of Form IXa from the suspension in 99.3% or greaterchemical purity as determined by high performance liquid chromatographicseparation of and quantitation by UV absorption at 254 nanometers. 41.Solid crystalline atorvastatin hemi-calcium and solvates thereofcharacterized by a powder X-ray diffraction pattern having peaks at 7.6,9.8, 16.5, 29.4±0.2 degrees two-theta.
 42. The solid crystallineatorvastatin hemi-calcium and solvates thereof of claim 41 furthercharacterized by peaks at 18.1, 20.0, 20.4, 21.9, 22.4 and 23.6±0.2degrees two-theta in its powder X-ray diffraction pattern.
 43. The solidcrystalline atorvastatin hemi-calcium and solvates thereof of claim 41further characterized by a powder X-ray diffraction pattern generatedusing CuK_(α) radiation substantially as depicted in FIG.
 15. 44. Aprocess for preparing solid crystalline atorvastatin hemi-calcium havingat least one characteristic of Form XIV and solvates thereof comprising:a) suspending atorvastatin hemi-calcium in water, and b) recovering theflakes from the suspension.
 45. The process of claim 44 wherein theatorvastatin hemi-calcium that is suspended is Form V.
 46. The processof claim 44 wherein the converting occurs over about 5 days.
 47. Theprocess of claim 44 wherein a fine suspended solid is formed about twoto about 10 hours after the atorvastatin hemi-calcium is suspended inwater.
 48. The process of claim 44 wherein the fine suspended solidconverts into flakes over from about one to about five days.
 49. Theprocess of claim 48 wherein conversion of the fine suspended solid intoflakes occurs over about five days.
 50. Solid crystalline atorvastatinhemi-calcium and solvates thereof characterized by powder X-raydiffraction pattern having peaks at 16.5, 21.9, 29.5±0.2 degreestwo-theta.
 51. The solid crystalline atorvastatin hemi-calcium andsolvates thereof of claim 50 further characterized by additional peaksat 7.7, 9.9, 16.5, 17.7, 18.3, 20.0, 21.9, 29.5±0.2 degrees two-theta inthe powder X-ray diffraction pattern.
 52. The solid crystallineatorvastatin hemi-calcium and solvates thereof of claim 50 furthercharacterized by a powder X-ray diffraction pattern generated usingCuK_(α) radiation substantially as depicted in FIG.
 16. 53. A processfor preparing solid crystalline atorvastatin hemi-calcium having atleast one characteristic of Form XVI and solvates thereof comprising: a)maintaining atorvastatin hemi-calcium Form XIV crystals at from about20° C. to about 50° C., and b) recovering the crystals as solidcrystalline atorvastatin hemi-calcium having at least one characteristicof Form XVI.
 54. The process of claim 53 wherein the atorvastatinhemi-calcium is maintained at about 22° C.
 55. The process of claim 53wherein the atorvastatin hemi-calcium is exposed to air while beingmaintained.
 56. Solid crystalline Atorvastatin hemi-calcium and solvatesthereof characterized by a powder X-ray diffraction pattern having peaksat 19.1, 20.6, 21.4 and 23.6±0.2 degrees two-theta.
 57. The solidcrystalline atorvastatin hemi-calcium and solvates thereof of claim 56further characterized by additional peaks at 7.8, 9.5, 10.2, 18.2, 19.1,25.3, 26.2, 30.1±0.2 degrees two-theta in the powder X-ray diffractionpattern.
 58. The solid crystalline atorvastatin hemi-calcium andsolvates thereof of claim 56 further characterized by a powder X-raydiffraction pattern generated using CuK_(α) radiation substantially asdepicted in FIG.
 17. 59. A process for preparing solid crystallineatorvastatin hemi-calcium having at least one characteristic of FormXVII and solvates thereof comprising: a) suspending atorvastatinhemi-calcium Form V in a mixture of about 96% ethanol and about 4%water, b) heating the suspension, c) cooling the suspension, and d)recovering solid atorvastatin hemi-calcium from the suspension having atleast one characteristic of Form XVII.
 60. The process of claim 59wherein the mixture is used in an amount of at least about 500 ml. 61.The process of claim 59 wherein the suspension is heated to about 78-80°C.
 62. A pharmaceutical composition comprising atorvastatin hemi-calciumselected from the group consisting of Forms IX, IXa, XIV, XVI, XVII andmixtures thereof and a pharmaceutically acceptable carrier.
 63. Use ofatorvastatin hemi-calcium selected from the group consisting of FormsIX, IXa, XIV, XVI, XVII and mixtures thereof to prepare a pharmaceuticaldosage form.
 64. A pharmaceutical dosage form comprising atorvastatinhemi-calcium selected from the group consisting of Forms IX, IXa, XIV,XVI, XVII and mixtures thereof.
 65. A method of reducing the plasma lowdensity lipoprotein level of a patient suffering from or susceptible tohypercholesterolemia by administering to the patient the pharmaceuticaldosage form of claim
 64. 66. Use of atorvastatin hemi-calcium selectedfrom the group consisting of Forms IX, IXa, XIV, XVI, XVII and mixturesthereof to prepare a pharmaceutical dosage form.
 67. A process forpreparing solid crystalline atorvastatin hemi-calcium having at leastone characteristic of Form I and solvates thereof comprising: a) heatingcrystals of atorvastatin hemi-calcium Form XIV to about 50° C. or above,and b) recovering the crystals as solid crystalline atorvastatinhemi-calcium having at least one characteristic of Form I.
 68. Theprocess of claim 67 wherein the atorvastatin hemi-calcium Form XIV isheated to about 65° C.
 69. A process for preparing solid crystallineatorvastatin hemi-calcium having at least one characteristic of FormVIII comprising: a) providing atorvastatin hemi-calcium Form XVII, b)drying the Form XVII to transform it into atorvastatin hemi-calciumhaving at least one characteristic of Form VIII, and c) recovering theatorvastatin having at least one characteristic of Form VIII.
 70. Theprocess of claim 69 wherein drying includes heating the Form XVII to anelevated temperature.
 71. The process of claim 70 wherein the elevatedtemperature is from about 40° C. to about 70° C.